Method of treating schizophrenia, depression and other neurological conditions

ABSTRACT

This application relates to the use of aminopiperazine derivatives for the treatment of schizophrenia, depression, and other neurological conditions.

This application is a 371 of PCT/JP97/04704, filed Dec. 19, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a new use of aminopiperazine derivatives andpharmaceutically acceptable salts thereof for the treatment and/orprevention of schizophrenia, depression, stroke; head injury, nicotinewithdrawal, spinal cord injury, anxiety, pollakiuria, incontinence ofurine, myotonic dystrophy, attention deficit hyperactivity disorder,excessive daytime sleepiness (narcolepsy), Parkinson's disease or autismin mammals

2. Description of the Background

The aminopiperazine derivatives used in this invention are known asdescribed in PCT International Publication No. WO 91/01979 that saidaminopiperazine derivatives possess the potentiation of the cholinergicactivity and are useful in the treatment of disorders in the centralnervous system for human beings, and more particularly in the treatmentof amnesia, dementia, senile dementia and the like.

SUMMARY OF THE INVENTION

The present invention relates to a new use of aminpiperazine derivativesand pharmaceutically acceptable salts thereof for the treatment and/orprevention of schizophrenia, depression, stroke, head injury, nicotinewithdrawal, spinal cord injury, anxiety, pollakiuria, incontinence ofurine, myotonic dystrophy, attention deficit hyperactivity disorder,excessive daytime sleepiness (narcolepsy), Parkinson's disease or autismfor mammals.

Accordingly, this invention is to provide a new use of aminopiperazinederivatives and pharmaceutically acceptable salts thereof for treatingand/or preventing schizophrenia, depression, stroke, head injury,nicotine withdrawal, spinal cord injury, anxiety, pollakiuria,incontinence of urine, myotonic dystrophy, attention deficithyperactivity disorder, excessive daytime sleepiness (narcolepsy),Parkinson's disease or autism.

Further, this invention is to provide an agent and a pharmaceuticalcomposition for treating and/or preventing schizophrenia, depression,stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety,pollakiuria, incontinence of urine, myotonic dystrophy, attentiondeficit hyperactivity disorder, excessive daytime sleepiness(narcolepsy), Parkinson's disease or autism, which comprises saidaminopiperazine derivatives and pharmaceutically acceptable saltthereof.

Still further, this invention is to provide a therapeutic method for thetreatment and/or prevention of schizophrenia, depression, stroke, headinjury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria,incontinence of urine, myotonic dystrophy, attention deficithyperactivity disorder, excessive daytime sleepiness (narcolepsy),Parkinson's disease or autism, which comprises administering said saidaminopiperazine derivatives and pharmaceutically acceptable saltsthereof to mammals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The aminopiperazine derivatives used in this invention can berepresented by the following general formula la [I]:

wherein R¹ is lower alkyl, aryl, ar(lower)alkoxy or a heterocyclicgroup, each of which may be substituted with halogen,

R² is hydrogen or lower alkyl,

R³ is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may besubstituted with halogen,

A is

—SO₂— or lower alkylene, and

Y is

—SO₂— or

and pharmaceutically acceptable salts thereof.

Said compound (I) and pharmaceutically acceptable salts thereof areuseful in the treatment and/or prevention of schizophrenia, depression,stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety,pallkiuria, incontinence of urine, myotonic dystrophy, attention deficithyperactivity disorder, excessive daytime sleepiness (narcolepsy),Parkinson's disease or autism in mammals.

Particulars of the various definitions mentioned in this specificationand preferred examples thereof are explained in the following.

The term “lower” is intended to mean a group having 1 to 6 carbonatom(s), unless otherwise provided.

Suitable “lower alkyl” may be a straight or branched one such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, orthe like, in which preferable one is methyl.

Suitable “aryl” may be phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl,and the like, Ln which preferable one is phenyl or naphthyl.

Suitable “ar(lower)alkoxy” may be benzyloxy, phenethyloxy,phenylpropoxy, benzhydryloxy, trityloxy and the like.

Suitable “heterocyclic group” may include saturated or unsaturated,monocyclic or polycyclic one containing at least one hetero atom such asnitrogen atom, oxygen atom or sulfur atom.

The preferred examples of thus defined “heterocyclic group” may be anunsaturated, 3 to 8-membered, more preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4-nitrogen atom(s), for example,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide,dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 5 nitrogenatom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated, 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,isoxazolyl, oxadiazolyl, etc.;

saturated, 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino,sydnonyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated, 3 to 8-membered heteromonoyclcic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl,isothiazolyl, thiadiazolyl, etc.;

unsaturated, 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s), for example, thienyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated, 3 to 8-membered heteromonocyclic group containing an oxygenatom, for example, furyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, etc.;

unsaturated, condensed heterocyclic group containing 1 to 2 oxygenatom(s), for example, benzofuranyl, etc.; or the like.

Suitable “cyclo(lower)alkyl” may be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Suitable “ar(lower)alkyl” may be benzyl, phenethyl, phenylpropyl,benzhydryl, trityl, and the like.

Suitable “lower alkylene” may be methylene, ethylene, propylene,pentamethylene, hexamethylene, and the like.

The above-mentioned “lower alkyl”, “aryl”, “ar(lower)alkoxy”,“heterocyclic group”, “cyclo(lower)alkyl” and “ar(lower)alkyl” may besubstituted with halogen [e.g. fluorine, chlorine, bromine and iodine].

Preferred compound [I] is one which has a lower alkyl, phenyl, naphthylor thienyl for R¹, hydrogen or lower alkyl for R², phenyl which may besubstituted with a halogen for R³,

for A, and

or —SO₂— for Y.

More preferred compound [I] is one which has a lower alkyl for Rhydrogen for R², phenyl which is substituted with a halogen for R³,

for A, and

for Y.

Most preferred compound [I] isN-(4-acetyl-1-piperazinyl)-4-fluorobenzamide.

Suitable pharmaceutically acceptable salts of the compound [I] areconventional non-toxic salts and include acid addition salt such as aninorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate,phosphate, etc.], an organic acid addition salt [e.g. formate, acetate,trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.], a salt with an amino acid [e.g. aspartic acidsalt, glutamic acid, salt, etc.] and the like.

It is to be noted that the compound [I] may include one or morestereoisomer(s) due to asymmetric carbon atoms, and all of such isomersand mixture thereof are included within the scope of this invention.

Additionally, it is to be noted that any hydrate of the compound [I] isalso included within the scope of this invention.

Now in order to show the utility of the compound [I] andpharmaceutically acceptable salts thereof in this invention, thepharmacological test was carried out and its abstract is shown in thefollowing.

The effect of the compound [I] upon cognitive function was examinedusing an operant delayed non-match to place paradigm (DNMTP) task whichis shown to be disrupted dose-dependently by the administration ofhaloperidol. The following interactions were explored: haloperidol plusamphetamine, haloperidol plus the compound [I] and haloperidol plus thecompound [I] and amphetamine. Neither a low dose of amphetamine nor twodoses of the compound [I] when administered with haloperidol, or alone,altered the profile of performance relative to control. The experimentswith haloperidol and the compound [I] plus amphetamine revealed aprofound attenuation of the deficits associated with increasing doses ofhaloperidol by the larger dose of the compound [I].

These experiments confirmed that the compound [I] has a specific effecton dopaminergic status which appears to be state dependent and is usefulfor treating and/or preventing schizophrenia, depression, stroke, headinjury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria,incontinence of urine, myotonic dystrophy, attention deficithyperactivity disorder, excessive daytime sleepiness (narcolepsy),Parkinson's disease or autism.

For therapeutic purpose, the compound [I] and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compounds, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral or parenteral administration. The pharmaceuticalpreparations may be capsules, tablets, dragees, granules, solution,suspension, emulsion, or the like. If desired, there may be included inthese preparations, auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

While the dosage of the compound [I] will vary depending upon the ageand condition of the patient, an average single dose of about 0.1 mg, 1mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I]may be effective for treating the above-mentioned diseases. In general,amounts between 0.1 mg/body and about 1,000 mg/body may be administeredper day.

The following Examples is given for the purpose of illustrating thisinvention.

EXAMPLE 1

(Capsule) N-(4-Acetyl-1-piperazinyl)-4-fluorobenzamide  5 mg Lactose 80mg

The above-mentioned ingredients were mixed and the mixture wasencapsulated to provide the capsule.

What is claimed is:
 1. A method of treating or preventing schizophrenia,depression, stroke, head injury, nicotine withdrawal, spinal cordinjury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy,attention deficit hyperactivity disorder, excessive daytime sleepiness(narcolepsy), Parkinson's disease or autism in a mammal, which comprisesadministering an effective amount of at least one of the followingcompounds of the formula (I) to a mammal in need thereof:

wherein: R¹ is lower alkyl, aryl, ar(lower)alkoxy or a heterocyclicgroup, each of which is optionally substituted with halogen; R² ishydrogen or lower alkyl; R³ is cyclo(lower)alkyl, aryl orar(lower)alkyl, each of which is optionally substituted with halogen; Ais

—SO₂— or lower alkylene; and Y is

—SO₂— or

or a pharmaceutically acceptable salt or hydrate thereof.
 2. The methodof claim 1, wherein said mammal is human.
 3. The method of claim 1,wherein in the formula (I), said heterocyclic group is a 3 to 8-memberedheterocyclic group containing at least one heteroatom selected from thegroup consisting of nitrogen, oxygen and sulfur atom.
 4. The method ofclaim 3, wherein in the formula (I), said heterocyclic group is a 5 or6-membered heteromonolic group containing 1 to 4 nitrogen atoms.
 5. Themethod of claim 4, wherein in the formula (I), said 5 or 6-memberedheterocyclic group is selected from the group consisting of pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl,tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,triazolyl, tetrazinyl, and tetrazolyl.
 6. The method of claim 3, whereinin the formula (I), said heterocyclic group is selected from the groupconsisting of indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, and benzotriazoyl.
 7. The method ofclaim 1, wherein in the formula (I), said heterocyclic group is a 3 to8-membered heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms.
 8. The method of claim 7, wherein in the formula (I),said heterocyclic group is selected from the group consisting ofoxazolyl, isoxazolyl, oxadiazolyl, and morpholino.
 9. The method ofclaim 3, wherein in the formula (I), said heterocyclic group isbenzoxazolyl or benzoxadiazolyl.
 10. The method of claim 3, wherein inthe formula (I), said heterocyclic group contains 1 to 2 sulfur atoms,and 1 to 3 nitrogen atoms.
 11. The method of claim 10, wherein in theformula (I), said heterocyclic group is selected from the groupconsisting of thiazolyl, isothiazolyl and thiadiazolyl.
 12. The methodof claim 3, wherein the formula (I), said heterocyclic group contains 1to 2 sulfur atoms.
 13. The method of claim 12, wherein in the formula(I), said heterocyclic group is thienyl.
 14. The method of claim 1,wherein in the formula (I), said heterocyclic group is selected from thegroup consisting of benzothiazolyl, benzothiadiazolyl, furyl,benzothienyl, and benzofuranyl.
 15. The method of claim 1, wherein inthe formula (I), said aryl of R¹ and R³ is independently selected fromthe group consisting of phenyl, naphthyl, tolyl, xylyl, mesityl andcumenyl.
 16. The method of claim 1, wherein in the formula (I), saidar(lower)alkyl of R³ is benzyl, phenethyl, phenylpropyl, benzhydryl ortrityl.
 17. The method of claim 1, wherein in the formula (I), saidar(lower)alkoxy of R¹ is benzyloxy, phenethyloxy, phenylpropoxyl,benzhydryloxy or trityloxy.
 18. The method of claim 1, wherein in theformula (I), R¹ is lower alkyl, phenyl, naphthyl or thienyl.
 19. Themethod of claim 1, wherein in the formula (I), R² is hydrogen or loweralkyl.
 20. The method of claim 1, wherein in the formula (I), R³ isphenyl optionally substituted with halogen.
 21. The method of claim 1,wherein in the formula (I), A is


22. The method of claim 1, wherein in the formula (I), Y is

or —SO₂.
 23. The method of claim 1, wherein in the formula (I), R₁ islower alkyl, R² is hydrogen, R³ is phenyl substituted with halogen, A is

and Y is


24. The method of claim 1, wherein the compound of the formula (I) is ahydrate.
 25. The method of claim 24, wherein the hydrate is amonohydrate.
 26. The method of claim 1, wherein the compound of theformula (I) is N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide hydrate. 27.The method of claim 26, wherein the compound of the formula (I) isN-(4-acetyl-1-piperazinyl)-4-fluorobenzamide monohydrate.
 28. The methodof claim 1, wherein said salt of the compound of the formula (I) is aninorganic or organic addition salt.
 29. The method of claim 1, whichfurther comprises administering an effective amount of amphetamine tosaid mammal.
 30. A pharmaceutical composition, which comprises: a) aneffective amount of at least one compound of claim 1, and b) aneffective amount of amphetamine.
 31. The pharmaceutical composition ofclaim 30, which further comprises a pharmaceutically-acceptable carrier.